RESUMEN
Influenza A virus (IAV) activates ZBP1-initiated RIPK3-dependent parallel pathways of necroptosis and apoptosis in infected cells. Although mice deficient in both pathways fail to control IAV and succumb to lethal respiratory infection, RIPK3-mediated apoptosis by itself can limit IAV, without need for necroptosis. However, whether necroptosis, conventionally considered a fail-safe cell death mechanism to apoptosis, can restrict IAV-or indeed any virus-in the absence of apoptosis is not known. Here, we use mice selectively deficient in IAV-activated apoptosis to show that necroptosis drives robust antiviral immune responses and promotes effective virus clearance from infected lungs when apoptosis is absent. We also demonstrate that apoptosis and necroptosis are mutually exclusive fates in IAV-infected cells. Thus, necroptosis is an independent, "stand-alone" cell death mechanism that fully compensates for the absence of apoptosis in antiviral host defense.
Asunto(s)
Caspasa 8/genética , Interacciones Microbiota-Huesped/genética , Virus de la Influenza A/inmunología , Necroptosis/genética , Infecciones por Orthomyxoviridae/inmunología , Inmunidad Adaptativa , Animales , Apoptosis/genética , Apoptosis/inmunología , Caspasa 8/metabolismo , Femenino , Técnicas de Sustitución del Gen , Interacciones Microbiota-Huesped/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Necroptosis/inmunología , Infecciones por Orthomyxoviridae/virología , Proteínas de Unión al ARN/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
RIPK3 induces necroptosis by phosphorylating MLKL, which then induces plasma membrane rupture and necrotic cell death. In this issue, Sai et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201810014) show that RIPK3-MLKL signaling in epithelial cells promotes Listeria clearance by directly suppressing cytosolic bacterial replication, without activating cell death.